{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:16:22Z","timestamp":1783653382460,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Suitable structural modifications of the functional groups at\n                    <jats:italic>N<\/jats:italic>\n                    \u2010substituent of (\u2212)\u2010\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010normetazocine nucleus modulate the affinity and activity profile of related ligands toward opioid receptors. Our research group has developed several compounds and the most interesting ligands,\n                    <jats:bold>LP1<\/jats:bold>\n                    and\n                    <jats:bold>LP2<\/jats:bold>\n                    , exhibited a dual\u2010target profile for mu\u2010opioid receptor (MOR) and delta\u2010opioid receptor (DOR). Recent structure\u2013affinity relationship studies led to the discovery of novel\n                    <jats:bold>LP2<\/jats:bold>\n                    analogs (compounds\n                    <jats:bold>1<\/jats:bold>\n                    and\n                    <jats:bold>2<\/jats:bold>\n                    ), which demonstrated high MOR affinity in the nanomolar range. Here, we reported the synthesis of the new (\u2212)\u2010\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010normetazocine derivatives (\n                    <jats:bold>3<\/jats:bold>\n                    \u2013\n                    <jats:bold>8<\/jats:bold>\n                    ) characterized by the absence of the phenyl ring in the\n                    <jats:italic>N<\/jats:italic>\n                    \u2010substituent compared to all previous reported ligands. Compounds\n                    <jats:bold>3<\/jats:bold>\n                    and\n                    <jats:bold>4<\/jats:bold>\n                    , featuring a methyl ester functional group in the\n                    <jats:italic>N<\/jats:italic>\n                    \u2010substituent, retained significant MOR affinity and exhibited similar affinity for the kappa\u2010opioid receptor (KOR). In contrast, compounds\n                    <jats:bold>7<\/jats:bold>\n                    and\n                    <jats:bold>8<\/jats:bold>\n                    , which contain a hydroxamic acid functionality, maintained affinity exclusively toward MOR. Neither of compounds (\n                    <jats:bold>3<\/jats:bold>\n                    \u2013\n                    <jats:bold>8<\/jats:bold>\n                    ) showed DOR affinity. Molecular modeling studies confirmed a similar docking pose in the MOR binding pocket for these compounds. Additionally, the in silico ADME profile of the most interesting ligands (\n                    <jats:bold>3<\/jats:bold>\n                    ,\n                    <jats:bold>4<\/jats:bold>\n                    ,\n                    <jats:bold>7<\/jats:bold>\n                    , and\n                    <jats:bold>8<\/jats:bold>\n                    ) was investigated revealing a favorable profile for compound\n                    <jats:bold>7<\/jats:bold>\n                    regarding the blood\u2013brain barrier permeability, suggesting its potential as a peripherally restricted opioid ligand.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70037","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T02:45:07Z","timestamp":1735267507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Evaluation of Novel (\u2212)\n                    <i>\u2010cis\u2010N\u2010<\/i>\n                    Normetazocine Derivatives: In\u00a0Vitro and\u00a0Molecular Modeling Insights"],"prefix":"10.1111","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-6371","authenticated-orcid":false,"given":"Giuliana","family":"Costanzo","sequence":"first","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4597-1025","authenticated-orcid":false,"given":"Alessandro","family":"Coco","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6185-5747","authenticated-orcid":false,"given":"Giuseppe","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0048-2631","authenticated-orcid":false,"given":"Vincenzo","family":"Patamia","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1412-2597","authenticated-orcid":false,"given":"Carmela","family":"Parenti","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4750-3479","authenticated-orcid":false,"given":"Emanuele","family":"Amata","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-8857","authenticated-orcid":false,"given":"Agostino","family":"Marrazzo","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5039-2151","authenticated-orcid":false,"given":"Antonio","family":"Rescifina","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1309-3368","authenticated-orcid":false,"given":"Lorella","family":"Pasquinucci","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  Catania 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